PROJECT SUMMARY Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathology is characterized by deposition of ?-amyloid and tau accumulations, leading to extensive neuron loss. The converging evidence from in vivo and in vitro studies support that aberrant behaviors of tau protein and their aggregation play a central role in the development of Alzheimer's disease pathology, but there is no experimental approach to control tau aggregation with great temporal and spatial precision. To address this fundamental issue, we have developed a new synthetic technique to optically control aggregation of pathogenic proteins upon light illumination. We propose to use this approach to control tau aggregation in order to model AD with human pluripotent stem cells (hiPSCs)-derived neurons. In future, our proposed studies will be complementary to existing animal models, and providing a novel platform for drug screening/validation. The optical control of tau aggregation will transform the current concepts of disease modeling and drug screening toward innovative translational approaches.